that the BMPR2 gene had undergone amutation in one of their patients.Additional research by both Trembath andscientists at Vanderbilt University furthersubstantiated these initial results.

Trembath observed that while the discovery of BMPR2 created an opportunityto better understand familial PPH, thebreakthrough also had implications for

Fall 2003W A L L C E N T E R U P D A T EN E W O P T I O N S N E W H O P E

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PRESORTEDFIRST-CLASS MAILU.S.POSTAGE PAID

PALO ALTO, CAPERMIT NO.28

750 Welch Road, Suite 305, Palo Alto, CA 94304-5731800.640.WALL (9255)

wallcenter@stanford.edu

V E R A M O U LT O N W A L L C E N T E R F O R P U L M O N A R Y V A S C U L A R D I S E A S E A T S T A N F O R D

monthlyPH Support Group 1st Tuesday of each month12:00 - 1:00pmModerator: Martha Russell, LCSWPlease RSVP to 650.724.9255Clinical Conference 2nd & 4th Monday of each month1:00 - 2:00pm (Lunch served)Please call 650.724.9255 for room location

septemberRace Against PH - 5K Run/WalkSunday, September 21, 2003; 9:00 am PH Support Group Tuesday, September 2Clinical Conference Monday, September 8

octoberPH Support Group Tuesday, October 7Clinical Conference Monday, October 13 & 27

novemberPH Support Group Tuesday, November 43rd Annual Evans Family LectureGuest Lecturer: Shaun R. Coughlin, M.D., Ph.D.Director, Cardiovascular Research Institute, Professor of Medicine and Cellular and MolecularPharmacology, UCSFThursday, November 6; 8:00 - 9:00 am, Fairchild AuditoriumClinical Conference Monday, November 10 & 24

decemberPH Support Group Tuesday, December 2Clinical Conference Monday, December 8

januaryPH Support Group Tuesday, January 6Clinical Conference Monday, January 12 & 26

februaryPH Support Group Tuesday, February 3Clinical Conference Monday, February 9 & 23

marchPH Support Group Tuesday, March 2Clinical Conference Monday, March 8 & 22

eneticists are the locksmiths ofthe medical world, using genes askeys to unveil the mysteries

behind disease. Richard C. Trembath,M.D., F.R.C.P., Professor of MedicalGenetics at the University of Leicester in theUnited Kingdom, discussed his discovery ofthe genetic key to primary pulmonary hypertension (PPH) at the third annualDunlevie Family Lecture at StanfordUniversity Medical Center.

Trembath’s interest in the pathogenesisof human disease was firmly establishedduring his undergraduate days at Guy’sHospital Medical School. His general medical training was followed by clinicaltraining in diabetes and endocrinology atSt. Bartholomew’s Hospital, as well asgenetic research in diabetes at the Instituteof Child Health. Today, he is an internationallyrenowned leader in the field of medicalgenetics who has published more than 100papers and abstracts. In addition to hisresearch in pulmonary vascular disease,Trembath and his team are also concernedwith conditions such as partial lipodystrophy,a disease in which abnormal fat depositsdevelop under the skin.

In his opening remarks, Trembath stated that a patient named Nicola firstpiqued his interest in the genetic causes ofPPH in 1992. The newly married Nicolaasked Trembath if he believed she was likelyto develop PPH, since three of her sistershad already died from the disease. She wasalso concerned about the possibility oftransmitting the gene for PPH to the children she planned to have. WhenTrembath attempted to research the answersto Nicola’s questions, he noted his effortstook only a “second” because there was “virtuallynothing known” about the genetic causes of PPH.

After assembling Nicola’s extendedfamily history, Trembath found what henow maintains is a classic case of familial, orinherited, PPH: more than 40 memberswithin her family appeared to be at 50-percentrisk of inheriting the gene to develop thedisease. By referring to the family historiesof other PPH patients, Trembath and hiscolleagues identified a region on chromosome2 that cosegregated with PPH in the majorityof the families they investigated. However,the team was still left with a fairly large areain which the gene could reside, since morethan 100 different locations within thatregion were potential candidates to carry thegene.

A fortuitous clinical observation freedTrembath from the painstaking work of sifting through all 100 locations. He discovered that in the mid-1980s, one NewZealand family contained two girls who hadbeen diagnosed with PPH and passed away;an extended family member had died fromthe condition as well. When Trembath visitedNew Zealand to research the case, he learnedmany members of the same family had suffered from another inherited vasculardisorder: hereditary hemorrhagic telangiectasia,or HHT. Trembath then realized a direct connection exists between PPH and HHT,since the same two genes on one chromosome 2 interval can be identified inboth diseases.

Upon further study of the same chromosome 2 interval, Trembath identifiedthe presence of a third gene-bone morphogenetic protein receptor type 2,(BMPR2), a gene that is known to aid inlung development. Thanks to the humangenome project, Trembath and his teamwere able to isolate the gene in 24 hours,gather their initial patient data, and confirm

The Third Annual Dunlevie Family Lecture in Pulmonary Medicine:

G

BMPR2:Genetic Key to PPH

Richard C. Trembath, M.D., F.R.C.P.

The Vera Moulton Wall Centerfor Pulmonary Vascular Disease

at Stanford

ucile Packard Children’s Hospital andStanford Hospital and Clinics are oneof the few combined centers in the

United States currently offering diagnosticand advanced therapeutic services to bothadults and children with pulmonary hypertension. In the fall of 2000, through thegenerous gift of an anonymous donor, theVera Moulton Wall Center for PulmonaryVascular Disease at Stanford was established.

The Wall Center seeks to serve as a leaderin both the clinical treatment and research ofpulmonary vascular disease, while also providingadvanced training opportunities forresearchers and clinicians. The Wall CenterUpdate is published biannually in the springand fall.

For Information, Consultation, or Referral:Toll-Free 800.640.WALL (9255)E-mail wallcenter@stanford.edu

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ome join us on the beautiful Stanford campus on September 21st at 9:00 a.m. for the third annual RACEAGAINST PULMONARY HYPERTENSION.

One of our core missions at the Vera Moulton Wall Center is to raise awareness about pulmonary hypertensionand help support research, which we hope will lead to a cure for this debilitating disease. This 5k fun run/walk is agreat way for the pulmonary hypertension community--patients, friends, family, and healthcare providers--to help.Proceeds from the race will benefit the Ewing Family Fund for Pulmonary Hypertension Research at Stanford.

We gratefully acknowledge the support of our corporate sponsors Actelion Pharmaceuticals, Accredo Therapeutics,JIBE Marketing, e-Agency, Studio 1.2.0.4, Andronico’s Market, Hobee’s California Restaurants, and Starbucks Coffee(University Avenue). If you or your company are interested in corporate sponsorship, there is still room for your support.

For additional information contact the Wall Center at 800.640.9255. To register on-line or make a donation visitwww.raceforph.org or www.active.com (keyword: PH race).

Hope to see you in September!

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Runners, Walkers, Volunteers, and

Supportive Bystanders Needed!!!

continued on page 3...

In the meantime, Trembath concluded,his research has had immediate consequencesfor patients like Nicola, who chose toundergo genetic testing nearly ten years following her first visit to Trembath. Afterlearning she hadn’t inherited the BMPR2mutation, Nicola gave birth to her firstchild in February 2002.

F A C U L T Y P R O F I L EWALL CENTER UPDATE - Fall 2003 Page 2 WALL CENTER UPDATE - Fall 2003 Page 3

r. John L. Faul is an AssistantProfessor and AttendingPhysician at Stanford University

Medical Center. Dr. Faul manages adultpatients with pulmonary arterial hypertension as well as patients who haveundergone heart-lung transplantation.

Dr. Faul was born in Dublin,Ireland. He received bachelor’s, master’s,medical, and doctorate degrees fromTrinity College in Dublin, Ireland. Aftercompleting his medical residency at St.James’s Hospital (Dublin), Dr. Faul conducted research in lung disease atJames Connolly Memorial Hospital(Dublin), the Royal Free Hospital(London), and Stanford University. Hehas received numerous international

awards for lung disease research, including the Cecil Lehman Research award from theAmerican College of Chest Physicians. In his free time, Dr. Faul enjoys modern art, tennis,golf, and running.

Dr. Faul’s research interests include the effects of anti-proliferative therapies on pulmonary arterial hypertension. “This is exciting work,” he says, “because it promises to lead to therapies that cure pulmonary hypertension rather than just improving symptoms.”

PH Research at StanfordWe currently have 3 clinical trials (one for adults, 2 for minors) open for enrollment.

Patients will receive study medication and study related testing free of charge during thestudy period. For additional information, please contact Val Scott at 650.725.8082.

Simvastatin (Zocor®)A Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Simvastatin onExercise Capacity in Patients with Pulmonary Hypertension.

This is a Stanford-initiated, randomized, double-blind, placebo-controlled studyof simvastatin in NYHA class II/III patients. Patients must be on Flolan or Remodulin® for at least 3 months. Simvastatin is currently FDA-approved for the treatment of high cholesterol. The study lasts 12 weeks and involves 4 visits to Stanford. During the study patients will have three 6 minute walk tests. This study is not open to patients currently on Tracleer®.

IV Sildenafil (Viagra®)A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel Group Study of Intravenous Sildenafil in the Treatment of Children, Aged 0 to 17 With Pulmonary Hypertension After Corrective Cardiac Surgery.

This study is open to patients 0-17 years of age with PHT after corrective cardiac surgery. The study starts after surgery and lasts for up to 2 days.

PO Sildenafil (Viagra®)A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel Group Study of Oral Sildenafil in the Treatment of Children, Aged 1 to 16 Years, With Pulmonary Arterial Hypertension.

This study is open to patients 1-16 of age with PAH secondary to congenital heart disease or collagen vascular disease. The study lasts 16 weeks andinvolves 6 visits to Stanford.

Caring for someone with PH can be diffi-cult, both physically and emotionally. If you area caregiver to a PH patient, try these strategies to maintain balance in your own lifewhile you continue to assist your loved one: ✚ Don’t give up the activities that are mostimportant to you, even if you have to modifythem.✚ Learn all you can about your loved one’s condition in order to provide the most meaningful help.✚ Have a backup caregiver lined up for timesyou are sick yourself, away from home, or justneed a break; you may also consider carryingthe number of a neighbor who is home duringthe day and could help out in an emergency.✚ Accept the offer of help from your family andfriends; be specific with them as to whatspecifically would be of help to you.✚ Counseling and a good support group canhelp you as much as they can help your lovedone; call the Pulmonary HypertensionAssociation (PHA) at (800)748-7274 to find thegroup nearest you.✚ If you have children, encourage them to helpout around the house.✚ Prioritize and accept the fact that somethings just won’t get done.✚ Hire a house cleaner, gardener, babysitter,or other support occasionally.✚ Order groceries on the Web; they’re oftendelivered right to your kitchen counter.✚ Encourage the patient to do the things he orshe is still capable of, such as mixing Flolanand filling pillboxes.✚ Love, honor and recognize yourself for thehard job you are doing.✚ Accept thanks graciously (this will be important to your loved one).✚ When in doubt as to how much to help, opena dialogue with your loved one.✚ Make time to “check-in” with yourself abouthow you are feeling, coping, etc.✚ Be alert to signs of depression and seek professional help if you need it.

PH patients can also assist their care-givers in maintaining a balanced life throughthe following steps:✚ Ask about the caregiver’s day; talk aboutcurrent events, the children, or favorite interests.✚ Try to take over some of the sedentary thingsthe caregiver must do, such as paying the bills,doing the taxes, or addressing holiday cards.✚ Let your support person know what yourneeds are specifically; open a dialogue aboutthese issues.✚ Remember to say “thank you” to your caregiver - it goes a long way.Adapted from the Pulmonary Hypertension Association’sPulmonary Hypertension: A Patient’s Survival Guide(Second Edition)

Caregiver

Caringfor the

DJohn L . Faul , M.D. , F.R.C.P.I . , F.C.C.P.

Ramona Doyle, M.D., Co-Director of theVera Moulton Wall Center for PulmonaryVascular Disease at Stanford and MedicalDirector of the University’s Heart andHeart-Lung Transplantation program, hadan entirely different philosophy towardstreatment than Mari’s doctors back home.While her other doctors simply told Marishe needed Flolan, Dr. Doyle explained whyshe needed Flolan and suggested additionaltreatment options. “I really appreciated theway the treatment was logically explained tome. It made sense,” notes Mari. “The mostimportant difference was Dr. Doyle’sencouragement to do what I could and listen to my body.” After returning to Japanand beginning Flolan treatment, Mari andher entire family eventually made the decision to move to California, where theycould be closer to Stanford.

Now a 20-year-old university student,Mari has transitioned to life in the UnitedStates, becoming proficient in a new language and making new friends. She credits the Wall Center doctors and staff formotivating her to live positively and encouraging her to watch her diet, maintainher weight, and exercise regularly. The combined efforts of Mari and her doctorshave paid off: her pulmonary pressures,which used to be over 100, were down to 50on her last echocardiogram. Mari’simproved health has allowed her to continue to do the things she enjoys most,such as watching movies, chatting withfriends, and taking walks.

“I guess I can’t be an astronaut anymore; I don’t think my lungs can handlethe altitude changes,” jokes Mari. However,she still dreams big dreams of entering themedical field one day. Above all, Mari ishappy that she can keep pursuing hergoals—even if it means wearing a pumpevery day.

ari Matsumura lived the typical,active life of a 17-year-old inKamakura, Japan. She was a

member of the tennis team and had bigdreams of becoming an astronaut or ecologist. So it seemed strange when climbingthe stairs grew increasingly difficult. Attimes, Mari experienced dizziness, shortnessof breath, and irregular heartbeats. Herfriends also noticed that Mari’s skin oftenlooked blue during tennis practice.

Then one day, Mari fainted in school.She quickly went to a local doctor, whotook an electrocardiogram (EKG) of herheart. As he reviewed the test results, Mariknew the doctor’s furrowed brow was a signof something very wrong. The doctorreferred her to a local cardiologist, who subsequently admitted Mari to the hospitalfor further testing.

“That was when I was the most afraid,”Mari remembers, “because they don’t keepyou in the hospital that long unless yourcondition is serious.” She received a heartcatheterization and a CT scan of her chest.Luckily, the cardiologist was then able toaccurately diagnose Mari’s condition as pulmonary hypertension (PH).

“The doctors kept telling me what thestatistics were in terms of survival, but thatdidn’t bother me,” recalls Mari. “Whatfrightened me was the thought of neverbeing active again. The only image I had ofsick people was one of confinement in bedand total dependence on others.”

Mari received another referral to a PHspecialist in Tokyo, who strongly urged herto go on Flolan—a medication that must becontinuously infused into the bloodstream.Mari would have to wear Flolan around herwaist in a pump, which would send thedrug inside her body via a permanent chestcatheter. She felt overwhelmed at thethought of the treatment. Mari wondered

how a person could live indefinitely with acatheter in her chest: swimming would beout of the question, and even her dailybathing routine would have to be modified.

Once Mari’s parents heard the diagnosis, they thought of StanfordUniversity Medical Center. Mari’s fatherhad attended the Stanford Graduate Schoolof Business years before, and he knew of theUniversity’s reputation as a leader in cutting-edge medical care and research.Despite her doctors’ cautious words againstflying, Mari traveled across the PacificOcean for a consultation at Stanford.

“It felt completely different to be seenby the doctors at Stanford,” Mari says.

M

Living Positivelyw i t h P u l m o n a r y H y p e r t e n s i o n

Although Trembath and his associateshave identified BMPR2 as the genetic keyto pulmonary hypertension, he cautionedthat many questions remain about the specific role the gene plays in the evolutionof the disease. He is currently using miceand other animal models to ascertain theanswers to these questions.

sporadic PH, or the disease as associatedwith other circumstances including AIDSand the use of appetite-suppressant drugs. Inone instance, Trembath related, a researcherrevealed males with sporadic PH have a 50-percent chance of carrying the BMPR2mutation.

Mari and her mother on a recent visit to Japan.

Trembath cont. from page 1